Dataset Information

B-lymphocyte-intrinsic and -extrinsic defects in secretory immunoglobulin A production in the neural crest-conditional deletion of endothelin receptor B model of Hirschsprung-associated enterocolitis.

ABSTRACT: Hirschsprung disease (HSCR) is a common cause of intestinal obstruction in the newborn. Hirschsprung-associated enterocolitis (HAEC) is a significant and life-threatening complication of HSCR, affecting up to 60% of patients. Animal models of endothelin receptor B (EdnrB) mutation reliably model human HSCR and HAEC. We previously demonstrated intestinal dysbiosis and a gut-specific deficiency of B-lymphocyte-produced secretory IgA (sIgA), the primary effector molecule of mucosal immunity, in mice with homozygous neural crest cell-conditional deletion of EdnrB (EdnrBNCC-/-). To determine mechanisms for sIgA deficiency, we examined intrinsic and extrinsic aspects of B-lymphocyte development and function. Expression of the endothelin axis components [endothelin-1 (ET-1), endothelin-3 (ET-3), endothelin receptor A (EdnrA), EdnrB] were determined over a developmental time course. B-lymphocyte survival and Ig production were assayed in vitro. Polymeric Ig receptor (pIgR)-mediated IgA transport into the intestinal lumen was interrogated. We found endothelin axis component (EdnrA, EdnrB, ET-1, ET-3) expression in developing extramedullary hematopoietic organs and that some splenic B lymphocytes express EdnrB. Splenic B lymphocytes from EdnrBNCC-/- mice showed no intrinsic defect in survival vs. wild-type (WT) B lymphocytes. In vitro stimulation of splenic B lymphocytes demonstrated decreased IgA, IgG, and IgM production in EdnrBNCC-/- vs. WT mice. Additionally, small intestinal pIgR was decreased ∼50% in EdnrBNCC-/- mice. These results suggest an intrinsic B-lymphocyte defect in antibody production as well as an extrinsic defect in IgA transport in the EdnrBNCC-/- model of HAEC. Our results are consistent with human HAEC observations of decreased luminal sIgA and mouse models of other inflammatory bowel diseases, in which decreased pIgR is seen in concert with a dysregulated microbiota. Finally, our results suggest targeting the dysbiotic microbiome and pIgR-mediated sIgA transport as potential therapeutic approaches in prevention and treatment of HAEC.-Medrano, G., Cailleux, F., Guan, P., Kuruvilla, K., Barlow-Anacker, A. J., Gosain, A. B-lymphocyte-intrinsic and -extrinsic defects in secretory immunoglobulinA production in the neural crest-conditional deletion of endothelin receptor B model of Hirschsprung-associated enterocolitis.

SUBMITTER: Medrano G

PROVIDER: S-EPMC6529339 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundHirschsprung-associated enterocolitis (HAEC) is a leading cause of serious morbidity and potential mortality in children with Hirschsprung's disease (HD). People with HAEC suffer from intestinal inflammation, and present with diarrhoea, explosive stools, and abdominal distension. Probiotics are live microorganisms with beneficial health effects, which can optimise gastrointestinal function and gut flora. However, the efficacy and safety of probiotic supplementation in the prevention of HAEC remains unclear.ObjectivesTo assess the effects of probiotic supplements used either alone or in combination with pharmacological interventions on the prevention of Hirschsprung-associated enterocolitis.Search methodsWe searched CENTRAL, PubMed, Embase, the China BioMedical Literature database (CBM), the World Health Organization International Clinical Trials Registry, ClinicalTrials.gov, the Chinese Clinical Trials Registry, Australian New Zealand Clinical Trials Registry, and Clinical Trials Registry-India, from database inception to 27 February 2022. We also searched the reference lists of relevant articles and reviews for any additional trails.Selection criteriaRandomised controlled trials (RCTs) comparing probiotics and placebo, or any other non-probiotic intervention, for the prevention of HAEC were eligible for inclusion.Data collection and analysisTwo review authors independently extracted data and assessed the risk of bias of the included studies; disagreements were resolved by discussion with a third review author. We assessed the certainty of evidence using the GRADE approach. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) for dichotomous outcomes.Main resultsWe included two RCTs, with a total of 122 participants. We judged the overall risk of bias as high. We downgraded the evidence due to risk of bias (random sequence generation, allocation concealment, and blinding) and small sample size. The evidence is very uncertain about the effect of probiotics on the occurrence of HAEC (OR 0.58, 95% CI 0.10 to 3.43; I² = 74%; 2 studies, 120 participants; very low-certainty evidence). We found one included study that did not measure serious adverse events and one included study that reported no serious adverse events related to probiotics. Probiotics may result in little to no difference between probiotics and placebo in relation to the severity of children with HAEC at Grade I (OR 0.66, 95% CI 0.14 to 3.16; I² = 25%; 2 studies, 120 participants; low-certainty evidence). The effects of probiotics on the severity of HAEC at Grade II are very uncertain (OR 1.14, 95% CI 0.01 to 136.58; I² = 86%; 2 studies, 120 participants; very low-certainty evidence). Similarly, the evidence suggests that probiotics results in little to no difference in relation to the severity of HAEC at Grade III (OR 0.43, 95% CI 0.05 to 3.45; I² = 0%; 2 studies, 120 participants; low-certainty evidence). No overall mortality or withdrawals due to adverse events were reported. Probiotics may result in little to no difference in the recurrence of episodes of HAEC compared to placebo (OR 0.85, 95% CI 0.24 to 3.00; 1 study, 60 participants; low-certainty evidence).Authors' conclusionsThere is currently not enough evidence to assess the efficacy or safety of probiotics for the prevention of Hirschsprung-associated enterocolitis when compared with placebo. The presence of low- to very-low certainty evidence suggests that further well-designed and sufficiently powered RCTs are needed to clarify the true efficacy of probiotics.

Project description:PurposeHirschsprung-associated enterocolitis (HAEC) is the most frequent potentially life-threatening complication in children with Hirschsprung disease (HSCR) even after definitive corrective surgery. Mounting evidence suggests that intestinal microbiota likely contribute to the etiology of enterocolitis, so the aim of this study was to use a mouse model of post pull-through HAEC to compare the fecal bacterial communities of animals which developed HAEC to those free of enterocolitis.MethodsTen Ednrb -/- and 8wild type mice underwent the microsurgical pull-through surgery, and stool was collected at the time of surgery, and then either at 2 and 4 weeks after the operation, or when the mice developed enterocolitis. The mid-colon of all animals was collected, prepared and histologically graded for enterocolitis. Fecal DNA was isolated and bacterial 16S rRNA genes analyzed using Illumina sequencing.ResultsSix Ednrb-/- mice developed HAEC with a mean enterocolitis score of 5.7, while the remaining 4 mutant and 8 WT mice remained free of enterocolitis by 4 weeks. The HAEC group had lower alpha diversity by Chao1 analysis compared with WT group, while the Ednrb-/- mice demonstrated distinct bacterial communities from WT mice on beta diversity analysis. The most striking finding was increased proportion of Akkermansia and reduced Bacteroidetes compared with the NO HAEC and WT groups, suggesting Akkermansia may contribute to development of enterocolitis while Bacteroidetes may be protective. Less abundant genera that were reduced in HAEC were Dysgonomas and Clostridium XIVa which may play a protective role.ConclusionsThis is the first study to identify Akkermansia as potentially playing a role in HAEC, either as a pathobiont taxa contributing to pathogenesis of enterocolitis, or possibly a protective commensal taxa expanded in response to inflammation. These findings characterized the dynamic shifts in the gut microbial communities through the onset of post pull-through HAEC, and suggests that there may be identifiable bacterial community differences in HSCR patients that are high risk for developing HAEC.

Project description:Hirschsprung's disease (HSCR) is characterized by aganglionosis from failure of neural crest cell (NCC) migration to the distal hindgut. Up to 40% of HSCR patients suffer Hirschsprung's-associated enterocolitis (HAEC), with an incidence that is unchanged from the pre-operative to the post-operative state. Recent reports indicate that signaling pathways involved in NCC migration may also be involved in the development of secondary lymphoid organs. We hypothesize that gastrointestinal (GI) mucosal immune defects occur in HSCR that may contribute to enterocolitis. EdnrB was deleted from the neural crest (EdnrBNCC-/-) resulting in mutants with defective NCC migration, distal colonic aganglionosis and the development of enterocolitis. The mucosal immune apparatus of these mice was interrogated at post-natal day (P) 21-24, prior to histological signs of enterocolitis. We found that EdnrBNCC-/- display lymphopenia of their Peyer's Patches, the major inductive site of GI mucosal immunity. EdnrBNCC-/- Peyer's Patches demonstrate decreased B-lymphocytes, specifically IgM+IgDhi (Mature) B-lymphocytes, which are normally activated and produce IgA following antigen presentation. EdnrBNCC-/- animals demonstrate decreased small intestinal secretory IgA, but unchanged nasal and bronchial airway secretory IgA, indicating a gut-specific defect in IgA production or secretion. In the spleen, which is the primary source of IgA-producing Mature B-lymphocytes, EdnrBNCC-/- animals display decreased B-lymphocytes, but an increase in Mature B-lymphocytes. EdnrBNCC-/- spleens are also small and show altered architecture, with decreased red pulp and a paucity of B-lymphocytes in the germinal centers and marginal zone. Taken together, these findings suggest impaired GI mucosal immunity in EdnrBNCC-/- animals, with the spleen as a potential site of the defect. These findings build upon the growing body of literature that suggests that intestinal defects in HSCR are not restricted to the aganglionic colon but extend proximally, even into the ganglionated small intestine and immune cells.

Dataset Information

B-lymphocyte-intrinsic and -extrinsic defects in secretory immunoglobulin A production in the neural crest-conditional deletion of endothelin receptor B model of Hirschsprung-associated enterocolitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets